Field of the Invention
The invention encompasses novel compounds and pharmaceutically acceptable salts thereof and compositions including therapeutically or prophylactically effective amounts of such compounds or pharmaceutically acceptable salts thereof.
Background of the Invention
The BRCA1 gene was identified in 1994 based its linkage to hereditary breast and ovarian cancers. BRCA1 mutations also confer an increased risk for several other hormone-responsive tumor types (cervical, endometrial, and prostate cancers). BRCA1 is a protein with 1863 amino acids and is considered to be a nuclear phospho-protein with conserved N-terminal RING and C-terminal acidic transcriptional activation domains. A BRCA1 null mutation confers early embryonic lethality (day 7.5-8.5) in mice, due to a severe proliferation defect caused by p53 activation and consequent p21WAF1 expression, but a partial BRCA1 deletion targeted to the mammary gland allows survival with development of breast cancer. In mice, BRCA1 expression is widespread, but it is especially increased in rapidly proliferating cells in compartments that are also undergoing differentiation, including mammary epithelial cells during puberty and pregnancy.
Various functional activities are ascribed to BRCA1, but it is still unclear which of these are essential for cancer suppression. Early studies indicated that BRCA1 is expressed and phosphorylated cyclically, suggesting a role in cell cycle regulation. BRCA1 was found to interact with RB1 and to collaborate with RB1 in regulating progression from G1 to S phase. Most studies on BRCA1 function, however, have concentrated on its role in DNA repair. In response to DNA damage, BRCA1 is phosphorylated by several up-stream protein kinases (ATM (ataxia-telangiectasia mutated), ATR, and CHEK2) and associates with the RMN complex (Rad50-Mre11-p95NBS1) in radiation-induced nuclear “dots,” suggesting a role in the repair of double-strand breaks. BRCA1 deficiency confers defects in several types of DNA repair mechanisms, including microhomology-dependent repair and homologous recombination. Studies of BRCA1 mutant cell types have also established roles for BRCA1 in several DNA damage-responsive cell cycle checkpoints (intra-S and G2/M). BRCA1 mutant cells exhibit evidence of genomic instability, e.g., centrosome amplification, aneuploidy, and chromosomal aberrations. In addition, BRCA1 is present in a large multi-protein BRCA1-associated genome surveillance complex (BASC). For these reasons, BRCA1 is thought to mediate a “caretaker” function in the maintenance of genomic stability.
Estrogen receptor-alpha (ER-α) is a member of the nuclear receptor superfamily of ligand activated transcription factors, characterized by: an N-terminal transactivation domain (AF-1), a conserved C-terminal activation domain (AF-2), which overlaps with the ligand binding domain (LBD), a sequence-specific DNA-binding domain (DBD), and a hinge region located between the DBD and AF-2 regions. BRCA1 is a strong inhibitor of E2-stimulated ER-α activity via a direct physical interaction with the AF-2 activation domain of ER-α. BRCA1 also represses ligand-independent activation of ER-α, since BRCA1-siRNA can stimulate ER-α activity in the absence of estrogen. This finding suggests that the endogenous levels of BRCA1 are sufficient to inhibit basal activity levels of ER-α. Further studies have documented that BRCA1 broadly inhibits E2-stimulated gene expression and blocks E2-stimulated proliferation of ER-α positive human breast cancer cells. BRCA1 has been detected at the ERE site of estrogen-regulated promoters (pS2 and cathepsin D), and exposure to E2 causes a rapid loss of BRCA1 from this site. Various breast cancer-associated BRCA1 mutations abrogate or greatly lessen the ability of BRCA1 to inhibit ER-α, suggesting that this function is essential for breast cancer suppression. Finally, it has recently been shown BRCA1 can inhibit the activity of aromatase (CYP19A1), a cytochrome P450 enzyme that mediates the conversion of androgens into estrogens, in epithelial cells and adipocytes.
About two-thirds of human sporadic (non-hereditary) breast cancers are ER-α positive, and hormonal factors clearly affect the risk for developing these tumors. In contrast to sporadic cancers, about two-thirds of BRCA1 mutant human breast cancers are ER-α negative. However, there is substantial evidence from clinical/epidemiologic studies and from experimental animal studies suggesting a hormonal etiology for BRCA1-mutant breast cancers, even though the tumors usually end up being ER-α negative.
For example, several studies provide evidence that BRCA1-mutant mammary carcinogenesis is estrogen-sensitive. For example, the chemoprevention agent Tamoxifen, which is a partial ER-α antagonist and agonist, can cause an increase in the prevalence of mammary hyperplasia and accelerated the development of mammary cancer in BRCA1Co/Co/MMTV-Cre/p53+/− mice. These findings were consistent with the finding that in MCF-7 cells, BRCA1 knockdown shifted the balance of Tamoxifen activity from ER-α antagonist to agonist. Moreover, in BRCA1Co/Co/MMTV-Cre/p53+/− mice, bilateral ovariectomy significantly reduced the incidence of mammary cancer. The ovariectomy was most effective in reducing cancer risk when performed well before the time the tumors normally occur. These results suggest that the early stages of BRCA1-dependent mammary tumorigenesis could be E2-dependent, and thus it may be possible to prevent or treat BRCA1-mutant breast cancers using an agent that can mimic the ability of BRCA1 to inhibit ER-α activity.